JP6683723B2 - 大動脈障害 - Google Patents
大動脈障害 Download PDFInfo
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- JP6683723B2 JP6683723B2 JP2017545680A JP2017545680A JP6683723B2 JP 6683723 B2 JP6683723 B2 JP 6683723B2 JP 2017545680 A JP2017545680 A JP 2017545680A JP 2017545680 A JP2017545680 A JP 2017545680A JP 6683723 B2 JP6683723 B2 JP 6683723B2
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Description
(i)例えば、そのマクロファージ受容体の活性立体構造を不安定にすること、及び/もしくは受容体をその不活性立体構造で維持し、それにより受容体がその天然リガンド、すなわち、GM−CSFに結合するのを防ぐことによって、GM−CSFシグナル伝達が達成されるGM−CSF受容体もしくはシグナル伝達分子の立体構造を変えること、
(ii)GM−CSFシグナル伝達が達成されるGM−CSF受容体に結合し、その受容体における伝達を防止、減少、もしくは減衰させること、
(iii)GM−CSF受容体に、もしくはGM−CSF自体に結合した負の調節因子によって活性化された下流シグナル伝達経路を下方調節もしくは非活性化すること、
(iv)GM−CSFの転写、翻訳、もしくは発現を減少、防止、もしくは減衰させること、
(v)GM−CSFの細胞内貯蔵からの合成もしくは放出を阻害すること、ならびに/または
(vi)GM−CSFの分解速度を増加させることを行うように構成され得る。
(i)試験対象から入手した試料中の、顆粒球マクロファージコロニー刺激因子(GM−CSF)、またはその変異型もしくは断片の濃度を検出するための検出手段と、
(ii)大動脈障害に罹患していない個体からの試料中の、GM−CSFの濃度に関する基準と、を含み、
このキットは、基準と比較して、試験対象からの身体試料中のGM−CSFの濃度の差を特定し、それにより試験対象が、大動脈障害に罹患している、もしくはそれに対する素因を有していることを示唆するか、または対象の病態の陰性予後を提供するように構成される。
マウス
ヘテロ接合性KLF6+/−マウス(C57BL/6)は、当初Tarocchiら(50)によって生成された。マクロファージ特異的KLF6ノックアウトマウスを生成するために、KLF6fl/flマウス(C57BL/6;129Sv)を、LysM Creマウス(C57BL/6、Jackson laboratory)と交雑した(51)。10〜13週齢の雄のマウスのみ、及び野生型マウスとしてC57BL/6(CLEA Japan)を使用した。全ての動物実験は、東京大学の動物実験委員会によって承認され、東京大学の動物実験に関するガイドラインを厳格に順守した。
大動脈解離/壁内血腫を誘導するために、CaCl2の大動脈周囲適用を腹部大動脈に対して行い、続いてAngIIを2週間注射した(2000ng kg−1min−1)(40)。詳細には、マウスに麻酔をかけ、10〜13週齢で開腹術を行った。腎動脈と腸骨動脈の分岐との間の腹部大動脈を、周囲の後腹膜構造から単離し、0.5MのCaCl2を腎臓下動脈の外面に適用した。疑似対照マウスにおいて、NaCl(0.9%)をCaCl2の代用とした。15分後に大動脈を0.9%無菌生理食塩水で洗浄し、切開を閉じた。
大動脈解離誘導の2日前、及び誘導の7日後、野生型マウスに、110mg kg−1のクロドロネートリポソームまたは等量のPBSリポソームを腹腔内注入した。GM−CSFに対する中和抗体(300μg、R&D systems)または対照抗ラットIgG抗体(Equitech Bio)を、腹腔内注入によって1日おきに投与した。組み換えマウスGM−CSF(10、50、100μg kg−1 day−1、PeproTech)を、大動脈解離の誘導後2週間または4週間にわたって投与した。
マウスからの大動脈を、パラフィンに埋め込み、次いで5μm厚の連続部分を、Elastic Von Gienson(EVG)及びヘマトキシリン/エオシン(HE)染色のために調製した。基準スケールを有するEVG染色した大動脈のデジタル画像を、直径の絶対測定に使用した。ヒト大動脈組織は、東京大学病院研究倫理委員会によって承認されたプロトコルに基づき、インフォームドコンセントを得て、大動脈修正手術を受けた患者から入手した。パラフィンに埋め込まれた部分を、EVG染色及び免疫組織化学のために大動脈から採取した。免疫組織化学の場合、脱パラフィン化及び遮断後、連続部分を以下の抗体を用いてインキュベートした。マウスにおけるマクロファージの場合、Mac−3(希釈1:200;ラット;BD Pharmingen)またはF4/80(1:100;ラット;Serotec)及びヒトにおいてCD68(1:50;マウス;DAKO)、ならびにGM−CSF(マウスの場合、1:100、ウサギ;Abcam、及びヒトの場合、1:50、ウサギ;Acris)またはp−STAT3(1:200;ウサギ;Cell Signaling Technology)、次いで、ビオチニル化二次抗体(1:200;DAKO)。検出のために、抗ストレプトアビジン複合AlexFluor 488またはAlexFluor 594(1:200;Invitrogen)を使用した。最終の連続洗浄後に、4′,6−ジアミジノ−2−フェニリンドール(1:5,000;Sigma−Aldrich)で核を染色した。
大動脈を3〜4mmの小片に刻み、Accumax(Innovative Cell Technologies)の基礎液中にコラゲナーゼII型(1.25mg mL−1、Worthington)及びブタ膵臓エラスターゼ(50μg mL−1、Worthington)を含有する1mLの消化液に入れた。大動脈組織を、1時間にわたって撹拌しながら室温で消化した。消化後、細胞をFACS緩衝液(PBS中5% FCS)中、2000rpmで5分間洗浄した。大動脈マクロファージを、製造者(Miltenyi Biotec)の指示に従い、CD11bマイクロビーズを使用して単離した。脾臓を均質化し、細胞濾し器を通して単一細胞懸濁液を得た。骨髄由来細胞は、5〜6週齢マウスの大腿骨及び脛骨から採取した。血液を、ヘパリンコーティングしたバイアル瓶に採取し、次いで1.2%デキストランを45分間にわたって室温で付加した。末梢白血球の計数は、自動血液分析装置(XT−2000i、Sysmex)によって行った。好中球を、製造者(Miltenyi Biotec)の指示に従い、好中球単離キットを使用して骨髄から単離した。脾臓、骨髄、及び血液の単一細胞懸濁液から、ACK溶解緩衝液を使用して、氷上でそれぞれ5分、3分、及び2分間にわたって赤血球を溶解した。細胞を、2000rpmで5分間遠心分離してACK溶解緩衝液を除去し、次いで単一細胞懸濁液を再懸濁し、FACS緩衝液中で洗浄し、続いて2000rpmで5分間遠心分離した。
骨髄由来細胞を、KLF6fl/flマウスまたはKLF6fl/fl;LysM Creマウスの大腿骨及び脛骨から調製して、マクロファージにおけるGM−CSFの役割を評価した。KLF6過剰発現を、RetroNectin(5μg/cm2、Takara Bio.)の存在下、KLF6(pMXs−KLF6)のためのレトロウイルス構築体によって誘導した。
マウスFc受容体は、マウスCD16/32抗原(eBioscience)に対する抗体を使用して、氷上で15分間遮断し、その後に細胞を洗浄し、次いで100 LのFACS緩衝液中に再懸濁した。APC−CD11b[M1/70]、PerCP−Cy5.5−Ly−6c[HK1.4]、APC−Cy7−Ly6G[1A8]、またはAPC−CD11c[N418]に対する蛍光色素複合抗体(全てBioLegendから)を、30〜45分間にわたって室温で付加した。FITC−CD3e[145−2C11]、FITC−Ly6G[RB6−8C5]、FITC−CD11b[M1/70]、FITC−CD45R/B220[RA3−6B2]、及びFITC−Ly76[Ter−119](赤血球系統マーカー)を、系統マーカーとして使用した。対応するアイソタイプ対照抗体を、関心対象の抗体と同じ濃度で試料に付加した。インキュベーション後に、試料を3回洗浄し、FACSverse(BD Pharmingen)によって分析した。単色染色された大動脈マクロファージを含有する陽性試料を使用して、補償を行った。低い順方向散乱によって定義される残屑及び死細胞は、分析から除外した。データを、FlowJo(Tree Star)により分析した。
ChIP分析を、製造者の指示に従い、クロマチン免疫沈降キット(Active Motif)を使用して行った。簡潔には、骨髄由来マクロファージを、1%ホルムアルデヒドとの10分間の架橋前に3時間にわたって、AngII(10μM)、TNFα(10ng mL−1)、及びIL−1β(20ng mL−1)を用いるか、または用いずに刺激した。クロマチンを、音波処理によって、200〜1000塩基対(Covaris)の平均サイズに剪断した。免疫沈降は、抗KLF6抗体(Santa Cruz Biotechnology)及びウサギIgG抗体(Santa Cruz Biotechnology)を使用して行った。KLF結合要素にまたがるGM−CSFプロモーター領域のPCR増幅は、以下のプライマー、順方向5′−AAGCCCTTCCAAGAACTGGC−3′(配列番号4)及び逆方向5′−GGCCCCTCAAAAAGGAGAGG−3′(配列番号5)を使用して行った。
KLF6動員は、入力DNAによって正規化し、KLF6抗体を有する対照群と比較した。
培養された細胞、大動脈マクロファージ、骨髄由来好中球、またはマウス大動脈試料からの全RNAを、製造者の指示に従い、RNeasyミニキット(Qiagen)またはRNAlater(Qiagen)のいずれかを使用して抽出した。0.5μg〜1μgのRNAを、製造者の指示に従い、Superscript III(Invitrogen)を使用して逆転写した。リアルタイムPCR反応を、SYBRグリーンIマスター(Roche)を含有する20μLの反応量当たり2μLの結果として生じるcDNAを使用して行った。GAPDHを、内部対照として使用した。AngII(10μM、3時間)刺激した骨髄由来マクロファージを使用して、RT2プロファイラーPCRアレイ(Qiagen)を、IL−6/STAT炎症経路に対する84個の関連遺伝子を用いて行った。PCRは、製造者の推奨手順に従い、LightCycler 480リアルタイムPCRシステム(Roche)上で行った。リアルタイムPCRプライマーは、表5に示される。
マウス大動脈標本を、プロテアーゼ阻害剤複合体(Roche)及びホスファターゼ阻害剤(Roche)を含有する溶解緩衝液(T−PER、Thermo Scientific)により均質化した。タンパク質濃度は、BCAタンパク質アッセイキット(Pierce)を使用してアッセイし、5マイクログラムのこのタンパク質を、10% NuPAGE(Invitrogen)によって溶解し、次いで二フッ化ポリビニリデン膜に移した。ブロットは、一次抗体;pSmad2(希釈1:400)、pERK1/2(1:3,000)、pSTAT3(1:3,000)、Smad2(1:1,000)、ERK1/2(1:3,000)、またはpSTAT3(1:3,000)(全てCell Signaling Technologyから入手されたウサギ抗体)、及び抗GAPDH抗体(Ambion)でプローブした。膜を洗浄し、対応するホースラディッシュペルオキシダーゼ複合二次抗体(Cell Signaling Technology)でインキュベートした。タンパク質バンドを、ECLplus(Thermo scientific)によって検出し、GAPDHは、タンパク質負荷のための内部対照として役割を果たした。
大動脈解離/壁内血腫を有するか、または有しないマウスまたはヒトにおけるIL−6、MCP−1、及びGM−CSFの血漿レベルは、商業的に入手可能なQuantikine ELISAキット(R&D systems)を用い、製造者の指示に従ってアッセイした。健康なボランティア及び大動脈瘤、冠動脈疾患、または大動脈解離を有する患者の血清は、東京大学病院研究倫理委員会によって承認されたプロトコルに基づき、インフォームドコンセントを得て入手した。ヒト対象のベースライン特徴は、表6に示される。
全てのデータは、平均±平均値の標準誤差として表される。2群間の統計的差異は、パラメトリックデータに関してはスチューデントt検定(両側)を用いて、またはノンパラメトリックデータに関してはマン・ホイットニー検定を用いて、F検定分析による正常性の試験後に決定した。複数の時点を含有するデータの場合、同時点での2群比較を行った。複数の群を比較する場合、ダンポスト検定を伴うクラスカル・ウォリスノンパラメトリック一元配置分散分析によってデータを分析した。カプラン・マイヤー法を使用して生存曲線を作成し、対数順位検定によって比較した。マウス実験の統計力は、Biomath(biomath.info/power)を使用して計算した。全ての試料サイズは、推奨される最小群のサイズ以上であった。全てのデータは、Prism 6.0(GraphPad Software)を使用して分析した。0.05未満のP値は、有意であると見なした。
実施例1−KLF6ヘテロ接合性ノックアウトマウスにおける炎症を伴う大動脈瘤
発明者らは、最初に、KLF6をヘテロ接合的に枯渇したマウスが、大動脈炎症を受けた場合[塩化カルシウム(CaCl2)の局所適用を伴う2週間のアンジオテンシンII(AngII)の注射]、悪化した大動脈瘤の表現型を呈することを見出した(保存大動脈壁を有する大動脈外径の50%超の増加として定義される)(21、22)。組織学的見出は、虚弱な大動脈壁を有する大動脈腔の拡大、及びさらには、マクロファージの顕著な浸潤と複合した線維組織(Mac3陽性細胞)の堆積を示した(図1a〜e)。機構的に、マトリックスメタロプロテアーゼ−9(MMP9、血管再構築のマーカーとして)(23)、F4/80(マクロファージのマーカーとして)(24、25)、及びIL−6(炎症のマーカーとして)(16、26〜30)の増加した発現が、大動脈内で見られた(図1f)。
KLF6欠乏マウスにおける大動脈病態が、マクロファージによる炎症性応答の調節不全に関与すると思われたため、骨髄特異的KLF6欠乏マウス(KLF6fl/fl;LysM Creマウス)をさらに生成し、対照マウスと比較して、70%の骨髄系統におけるKLF6発現の特異的低減を示した。大動脈炎症を受けたKLF6fl/fl;LysM Creマウスは、ヘテロ接合性ノックアウトマウスにおいて見られるものと同様の悪化した腹部大動脈瘤の表現型を示したが、興味深いことに、解離3の内膜断裂に付随する血腫形成を伴う大動脈内壁の分離として定義される、上行腎大動脈解離/壁内血腫をさらに示した(図6)。この病変はまた、Mac3陽性マクロファージの浸潤を伴う線維組織の堆積を示し(図2b〜e及び図7a、b)、故に、KLF6欠乏の大動脈表現型が、炎症性応答の混乱と関連していたことを確認する。死亡したマウスは、大動脈解離/壁内血腫に続いて、大動脈破裂に起因する可能性が高かった(図2a)。
次に、標的分子及び免疫細胞の調節機序の描写を、RNAプロファイリングアレイ分析を使用して説明した。注目すべきことに、GM−CSFレベルは、対照マクロファージと比較して、AngII刺激(3.89倍)に応答して、KLF6fl/fl;LysM Creマウスの骨髄由来のマクロファージにおいて最大増加を示した(図3a)。
次に、これらのマウスの大動脈解離におけるGM−CSFの要件を試験するために、大動脈解離/壁内血腫(図4a、b)、ならびにIL−6の血清レベル(図4c)に加えて、GM−CSF受容体α、MMP9、F4/80、及びIL−6の発現(図4d)を排除する中和抗体を使用して、GM−CSFの作用を遮断した。したがって、GM−CSFは、KLF6fl/fl;LysM Creマウスにおける大動脈表現型に必要とされた。
これらの見出の臨床的関連を確認するために、急性大動脈解離を有する患者の血清中でGM−CSFの循環レベルを測定したところ、冠動脈疾患、大動脈瘤を有する患者、または無視できないが顕著に低いレベルを示した健康なボランティアとは対照的に、顕著な増加を示した(図5a)。さらに、炎症性浸潤(CD68+単球/マクロファージ)及びGM−CSF発現は、解離された大動脈において上方調節され、共存していた(図5b)。故に、GM−CSFは、マウスにおいてのみならず、ヒト病態においても急性大動脈解離と関連付けられる。
本見出は、GM−CSFが、この病態のマウスモデルにおいて大動脈解離/壁内血腫を引き起こし、ヒトにおける病態とも関連付けられる重要な調節分子であることを示す。マウスにおいて、中和抗体または外因性投与それぞれによるGM−CSFの調節は、この表現型の発症を予防または誘導した。ヒトにおいて、大動脈組織中の上昇した血清GM−CSFレベル及びサイトカインの発現が、大動脈解離を有する患者において見られた。
大動脈解離及び壁内血腫は、大動脈壁の分離を伴う大動脈障害を含む。この病態の根底にある機序は、依然として不明である。ここで発明者らは、顆粒球マクロファージコロニー刺激因子(GM−CSF)が、この病態の誘発分子であることを示す。転写因子クルッペル様因子6(KLF6)−骨髄特異的条件付き欠乏マウスは、大動脈炎症を受けた場合に、この大動脈表現型を呈した。機構的に、KLF6は、GM−CSFの発現及び分泌を下方調節した。GM−CSFに対する中和抗体の投与は、これらのマウスにおいて病態を予防した。逆に、野生型マウスへの、大動脈炎症と組み合わせたGM−CSFの投与は、効果の大まかな性質を示唆する表現型を誘導するのに十分であった。さらに、この病態を有する患者は、GM−CSFの高度に増加した循環レベルを示し、これは解離された大動脈においても局所的に発現された。したがって、GM−CSFは、この大動脈障害を引き起こす重要な調節分子であり、このサイトカインの調節は、この病態のための活用可能な治療戦略である。
1 Nienaber.C.A.&Powell.J.T.Management of acute aortic syndromes.Eur Heart J 33.26−35b(2012).
2 Tsai.T.T..Nienaber.C.A.&Eagle.K.A.Acute aortic syndromes.Circulation 112.3802−3813(2005).
3 Hiratzka.L.F.et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease.A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.American Association for Thoracic Surgery.American College of Radiology,American Stroke Association.Society of Cardiovascular Anesthesiologists.Society for Cardiovascular Angiography and Interventions.Society of Interventional Radiology.Society of Thoracic Surgeons,and Society for Vascular Medicine.J Am Coll Cardiol 55.e27−e129(2010).
4 Hagan.P.G.et al.The International Registry of Acute Aortic Dissection(IRAD):new insights into an old disease.JAMA 283.897−903(2000).
5 Suzuki.T.et al.Biomarkers of aortic diseases.Am Heart J 165.15−25(2013).
6 Suzuki.T..Distante.A.&Eagle.K.Biomarker−assisted diagnosis of acute aortic dissection:how far we have come and what to expect.Curr Opin Cardiol 25.541−545(2010).
7 Clough.R.E.&Nienaber.C.A.Management of acute aortic syndrome.Nature reviews.Cardiology doi:10.1038(2014).
8 Song.J.K.Aortic intramural hematoma:aspects of pathogenesis 2011.Herz 36.488−497(2011).
9 von Kodolitsch.Y.et al.Intramural hematoma of the aorta:predictors of progression to dissection and rupture.Circulation 107.1158−1163(2003).
10 Milewicz.D.M..Regalado.E.S.&Guo.D.C.Treatment guidelines for thoracic aortic aneurysms and dissections based on the underlying causative gene.J Thorac Cardiovasc Surg 140.S2−4; discussion S45−51(2010).
11 Milewicz.D.M.et al.Genetic basis of thoracic aortic aneurysms and dissections:focus on smooth muscle cell contractile dysfunction.Annu Rev Genomics Hum Genet 9.283−302(2008).
12 Holm.T.M.et al.Noncanonical TGFbeta signaling contributes to aortic aneurysm progression in Marfan syndrome mice.Science 332.358−361(2011).
13 Li.W.et al.Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis.J Clin Invest 124.755−767(2014).
14 Dietz.H.C.TGF−beta in the pathogenesis and prevention of disease:a matter of aneurysmic proportions.J Clin Invest 120.403−407(2010).
15 Ju.X.et al.Interleukin−6−signal transducer and activator of transcription−3 signaling mediates aortic dissections induced by angiotensin II via the T−helper lymphocyte 17−interleukin 17 axis in C57BL/6 mice.Arterioscler Thromb Vasc Biol 33.1612−1621(2013).
16 Tieu.B.C.et al.An adventitial IL−6/MCP1 amplification loop accelerates macrophage−mediated vascular inflammation leading to aortic dissection in mice.J Clin Invest 119.3637−3651(2009).
17 Date.D.et al.Kruppel−like transcription factor 6 regulates inflammatory macrophage polarization.J Biol Chem 289.10318−10329(2014).
18 Starkel.P.et al.Oxidative stress.KLF6 and transforming growth factor−beta up−regulation differentiate non−alcoholic steatohepatitis progressing to fibrosis from uncomplicated steatosis in rats.J Hepatol 39.538−546(2003).
19 Holian.J.et al.Role of Kruppel−like factor 6 in transforming growth factor−beta1−induced epithelial−mesenchymal transition of proximal tubule cells.Am J Physiol Renal Physiol 295.F1388−1396(2008).
20 Hamilton.J.A.&Anderson.G.P.GM−CSF Biology.Growth Factors 22.225−231(2004).
21 Daugherty.A..Manning.M.W.&Cassis.L.A.Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E−deficient mice.J Clin Invest 105.1605−1612(2000).
22 Johnston.K.W.et al.Suggested standards for reporting on arterial aneurysms.Subcommittee on Reporting Standards for Arterial Aneurysms.Ad Hoc Committee on Reporting Standards.Society for Vascular Surgery and North American Chapter.International Society for Cardiovascular Surgery.J Vasc Surg 13.452−458(1991).
23 Nagasawa.A.et al.Important role of the angiotensin II pathway in producing matrix metalloproteinase−9 in human thoracic aortic aneurysms.J Surg Res 183.472−477(2013).
24 Ezekowitz.R.A.&Gordon.S.Down−regulation of mannosyl receptor−mediated endocytosis and antigen F4/80 in bacillus Calmette−Guerin−activated mouse macrophages.Role of T lymphocytes and lymphokines.J Exp Med 155.1623−1637(1982).
25 Ezekowitz.R.A..Austyn.J..Stahl.P.D.&Gordon.S.Surface properties of bacillus Calmette−Guerin−activated mouse macrophages.Reduced expression of mannose−specific endocytosis.Fc receptors.and antigen F4/80 accompanies induction of Ia.J Exp Med 154.60−76(1981).
26 Atreya.R.et al.Blockade of interleukin 6 trans signaling suppresses T−cell resistance against apoptosis in chronic intestinal inflammation:evidence in crohn disease and experimental colitis in vivo.Nat Med 6.583−588(2000).
27 Cheuk.B.L.&Cheng.S.W.Can local secretion of prostaglandin E2.thromboxane B2.and interleukin−6 play a role in ruptured abdominal aortic aneurysm? World J Surg 32.55−61(2008).
28 Dawson.J.et al.Aortic aneurysms secrete interleukin−6 into the circulation.J Vasc Surg 45.350−356(2007).
29 Dawson.J..Cockerill.G..Choke.E..Loftus.I.&Thompson.M.M.Aortic aneurysms as a source of circulating interleukin−6.Ann N Y Acad Sci 1085.320−323(2006).
30 Treska.V..Topolcan.O.&Pecen.L.Cytokines as plasma markers of abdominal aortic aneurysm.Clin Chem Lab Med 38.1161−1164(2000).
31 Wright.H.L..Moots.R.J..Bucknall.R.C.&Edwards.S.W.Neutrophil function in inflammation and inflammatory diseases.Rheumatology 49.1618−1631(2010).
32 Habashi.J.P.et al.Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism.Science 332.361−365(2011).
33 Lindsay.M.E.et al.Loss−of−function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm.Nat Genet 44.922−927(2012).
34 Sawaki.D.&Suzuki.T.Targeting transforming growth factor−beta signaling in aortopathies in Marfan syndrome.Circ J 77.898−899(2013).
35 Feng.X.H.&Derynck.R.Specificity and versatility in tgf−beta signaling through Smads.Annu Rev Cell Dev Biol 21.659−693(2005).
36 Shindo.J.et al.Granulocyte−macrophage colony−stimulating factor prevents the progression of atherosclerosis via changes in the cellular and extracellular composition of atherosclerotic lesions in watanabe heritable hyperlipidemic rabbits.Circulation 99.2150−2156(1999).
37 Zhu.S.N..Chen.M..Jongstra−Bilen.J.&Cybulsky.M.I.GM−CSF regulates intimal cell proliferation in nascent atherosclerotic lesions.J Exp Med 206.2141−2149(2009).
38 Haghighat.A..Weiss.D..Whalin.M.K..Cowan.D.P.&Taylor.W.R.Granulocyte colony−stimulating factor and granulocyte macrophage colony−stimulating factor exacerbate atherosclerosis in apolipoprotein E−deficient mice.Circulation 115.2049−2054(2007).
39 Ye.P.et al.GM−CSF contributes to aortic aneurysms resulting from SMAD3 deficiency.J Clin Invest 123.2317−2331(2013).
40 Kimura.T.et al.Tenascin C protects aorta from acute dissection in mice.Sci Rep 4.4051(2014).
41 Weissen−Plenz.G.et al.Aortic dissection associated with Cogans’s syndrome:deleterious loss of vascular structural integrity is associated with GM−CSF overstimulation in macrophages and smooth muscle cells.J Cardiothorac Surg 5.66(2010).
42 Kessel.A..Vadasz.Z.&Toubi.E.Cogan syndrome − Pathogenesis.clinical variants and treatment approaches.Autoimmun Rev 13.351−354(2014).
43 Babamusta.F.et al.Angiotensin II infusion induces site−specific intra−laminar hemorrhage in macrophage colony−stimulating factor−deficient mice.Atherosclerosis 186.282−290(2006).
44 Brocheriou.I.et al.Antagonistic regulation of macrophage phenotype by M−CSF and GM−CSF:implication in atherosclerosis.Atherosclerosis 214.316−324(2011).
45 Filonzi.E.L..Zoellner.H..Stanton.H.&Hamilton.J.A.Cytokine regulation of granulocyte−macrophage colony stimulating factor and macrophage colony−stimulating factor production in human arterial smooth muscle cells.Atherosclerosis 99.241−252(1993).
46 Sakai.M.et al.Glucocorticoid inhibits oxidized LDL−induced macrophage growth by suppressing the expression of granulocyte/macrophage colony−stimulating factor.Arterioscler Thromb Vasc Biol 19.1726−1733(1999).
47 Plenz.G..Koenig.C..Severs.N.J.&Robenek.H.Smooth muscle cells express granulocyte−macrophage colony−stimulating factor in the undiseased and atherosclerotic human coronary artery.Arterioscler Thromb Vasc Biol 17.2489−2499(1997).
48 Saraff.K..Babamusta.F..Cassis.L.A.&Daugherty.A.Aortic dissection precedes formation of aneurysms and atherosclerosis in angiotensin II−infused.apolipoprotein E−deficient mice.Arterioscler Thromb Vasc Biol 23.1621−1626(2003).
49 Cavalcante.J.L..Lima.J.A..Redheuil.A.&Al−Mallah.M.H.Aortic stiffness:current understanding and future directions.J Am Coll Cardiol 57.1511−1522(2011).
50 Tarocchi.M.et al.Carcinogen−induced hepatic tumors in KLF6+/− mice recapitulate aggressive human hepatocellular carcinoma associated with p53 pathway deregulation.Hepatology 54.522−531(2011).
51 Clausen.B.E..Burkhardt.C..Reith.W..Renkawitz.R.&Forster.I.Conditional gene targeting in macrophages and granulocytes using LysMcre mice.Transgenic Res 8.265−277(1999).
Claims (8)
- 抗顆粒球マクロファージコロニー刺激因子(GM−CSF)抗体またはその抗原結合断片を含む、大動脈解離または大動脈壁内血腫の進行もしくは再発の治療、予防、または改善剤。
- 前記抗GM−CSF抗体またはその抗原結合断片が、急性大動脈解離の一次修正手術を受けた対象における再発性大動脈解離を予防するために、または慢性大動脈解離を有する対象における大動脈解離の進行を予防するために使用される、請求項1に記載の治療、予防、または改善剤。
- 前記抗GM−CSF抗体またはその抗原結合断片が、配列番号2、またはその変異型もしくは断片に特異的に結合する、請求項1または2に記載の治療、予防、または改善剤。
- 前記抗GM−CSF抗体またはその抗原結合断片が、配列番号3、またはその変異型もしくは断片に特異的に結合する、請求項1〜3のいずれか1項に記載の治療、予防、または改善剤。
- 前記抗GM−CSF抗体またはその抗原結合断片が、モノクローナル抗体またはその抗原結合断片を含む、請求項1〜4のいずれか1項に記載の治療、予防、または改善剤。
- 前記抗体が、ヒトまたはヒト化抗体である、請求項1〜5のいずれか1項に記載の治療、予防、または改善剤。
- 請求項1〜6のいずれか1項に記載の抗顆粒球マクロファージコロニー刺激因子(GM−CSF)抗体またはその抗原結合断片、及び必要に応じて薬学的に許容されるビヒクルを含む、大動脈解離または大動脈壁内血腫の進行もしくは再発の治療の薬学的組成物。
- 治療上有効な量の請求項1〜6のいずれか1項に記載の抗GM−CSF抗体またはその抗原結合断片を、薬学的に許容されるビヒクルと複合することを含む、請求項7に記載の薬学的組成物の作製プロセス。
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